This invention relates to a novel process for the preparation of 2-bromo-8-ergolinyl compounds.
2-bromo-8-ergolinyl compounds are important drugs from the series of ergot alkaloids such as, for example, the known bromocriptine for the treatment of hyperprolactinemia (H. R. Schneider et al. Experientia 33 (1977) 1412) or 2-bromolisuride (EPA 0056 358). However, they can also be used as intermediates for the production of pharmacologically active ergot alkaloids, e.g., 9,10-didehydro-6-methylergoline-8.alpha.-amine according to the procedure of U.S. Ser. No. 452,521 and 9,10-didehydro- 6-methylergoline-8.alpha.-carboxylic acid amide according to the procedure described in U.S. Ser. No. 415,612 for the production of bromerguride.
Bromination methods for ergot alkaloids have been known for some time (see, for example, F. Troxler and A. Hofmann, Helv. Chim. Acta 40 : 2160 [1957]). According to this classic process, moderate yields of lysergic acid derivatives are obtained under heating with 1.2-1.5 molar equivalents of N-bromosuccinimide in dioxane, forming the corresponding 2-bromo compounds. Numerous suitability tests have been conducted in the past on a great variety of brominating agents, such as dioxane dibromide, N-bromocaprolactam, or N-bromophthalimide (for example, DOS 1,926,045).
Other selective brominating agents for this purpose are, for example, the bromine addition complexes 2-pyrrolidone hydrotribromide (DOS 2,752,532) and 3-bromo-6-chloro-2-methylimidoazo[1,2-b]pyridazine hydrotribromide (DOS 2,938,313).
All of these brominating methods have the disadvantage that, on the one hand, the yields of desired bromination product are not quantitative and, on the other hand, the bromination product frequently requires a technically rather expensive procedure for separating it from the corresponding carrier compounds formed from the brominating reagents employed and present in the reaction mixture.